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Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In summary, this case illustrates a previously unrecognized syndrome of reticulocytosis secondary to a defect in reticulin degradation. We are aware of two other case reports in the literature which also describe patients with an elevated reticulocyte count who's red cells appeared to lack the ability to degrade reticulin (Lofters et. al.1978, Tulliez et. al. 1982). Both of these cases however, demonstrated only mild reticulocytosis and appeared to be related to preleukemic syndromes. Our patient had no evidence of preleukemia and indeed, has been followed for over four years without evidence of other hematologic abnormalities. The mild anemia that has persisted in this patient may suggest that although no evidence of hemolysis is obvious in this patient, some minor amount of hemolysis may be occurring. Due to the relative insensitivity of other measures of early red cell death (51Cr survival, bone marrow biopsy, etc...), and the loss of the the reticulocyte count as a sensitive index of hemolysis, a minor amount of hemolysis cannot be excluded. This does not decrease the validity of the observations noted above, since this massive reticulocytosis cannot be explained by minimal hemolysis. Whether this patient's reticulocytosis represents an acquired or congenital syndrome is unsettled at present. Although his brother is unaffected, and we have on record only a mildly elevated reticulocyte count from 1981, there remains a possibility that this syndrome is congenital. We are, at present, in the process of further characterizing the specific defect in these red cells. Further assays of Lipoxygenase and protease activity, the ability to ubiquitinate proteins, specific identification of the mitochondria-like structures, and protein synthesis assays are in progress or are planned. The inability to degrade reticulin in this patient's red cells and the impact of this upon other cellular physiologic processes afford an excellent opportunity to enhance our understanding of normal red cell physiology, particularly, we suspect in this patient, of Ubiquitin-ATP-dependent proteolysis.
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PMID:Reticulocytosis: defective reticulin degradation, a case report. 248 76

Cleavage of the two carboxyl-terminal glycine residues from native ubiquitin yields the proteolysis-incompetent derivative des-Gly-Gly-ubiquitin. We report here that this derivative inhibits the ATP-dependent degradation of casein and is multi-ubiquitinated but not degraded by reticulocyte lysates. Inhibition of proteolysis diminished with increasing concentration of native ubiquitin, but was not reduced by increased casein concentration. Cleavage of the last four residues from ubiquitin yielded a derivative that was a weaker inhibitor of proteolysis and a poorer substrate for ubiquitination. These results suggest that the conjugation of ubiquitin to ubiquitin during polyubiquitin synthesis involves a specific conjugation system that recognizes ubiquitin and some of its derivatives, but not general proteolysis substrates, as ubiquitin acceptors.
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PMID:Inhibition of ubiquitin-dependent proteolysis by des-Gly-Gly-ubiquitin: implications for the mechanism of polyubiquitin synthesis. 254 56

Since its discovery in 1956 the physiological function of the ATP-dependent proteolysis in reticulocytes has become an area of intensive interest. The evidence that mitochondria are the main substrate of the process during maturation of reticulocytes is summarized. The large consumption of ATP related to the degradation of mitochondria is discussed in context with possible mechanisms for ATP requirement. A novel ATP-dependent peptide release from reticulocyte mitochondria, which may be the first step in the degradation of the organelles, is demonstrated. Ubiquitin and tRNA are involved in the degradation process. Their roles, however, are not yet clear. The whole degradation cascade consisting of lipoxygenase, mitochondria susceptibility factor and ATP-dependent proteolysis, may function as a defense system against uncontrolled degradation of mitochondria in reticulocytes.
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PMID:ATP-dependent proteolysis of mitochondria of reticulocytes. 256 99

Degradation of intracellular proteins via the ubiquitin system involves several steps. Initially, ubiquitin is covalently linked to the protein substrate in an ATP-dependent reaction. Following ubiquitin conjugation, the protein is selectively degraded with the release of free and reutilizable ubiquitin. Ubiquitin modification of a variety of protein targets within the cell appears to be important in a number of basic cellular functions. For example, modification of core nucleosomal histones may regulate gene expression at the level of chromatin structure. Ubiquitin attachment to cell surface proteins can play a role in the processes of cell-cell interaction and adhesion. Conjugation of ubiquitin to other, yet to be identified protein(s), is probably involved in the progression of cells from one stage to another in the cell cycle. Despite the considerable progress that has been made in elucidating the mode of action and roles of the ubiquitin pathway major problems remain unsolved. One problem of central importance is the issue of what determines the specificity of the ubiquitin ligation system for commitment of certain proteins to degradation. While a free alpha-amino group is one structural feature of the substrate recognized by the ligation system, it is certainly not the only one, and possibly not the predominant recognition marker. The scope of this review is to discuss recent developments in our understanding of the specificity and selection of substrates for conjugation and subsequent degradation via the ubiquitin system.
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PMID:The ubiquitin-dependent proteolytic pathway: specificity of recognition of the proteolytic substrates. 256 43

Ubiquitin is a 76-amino acid protein whose sequence is highly conserved throughout evolution from invertebrates to mammals. It is both a cytoplasmic and nuclear protein. In the cytoplasm it is involved in ATP-dependent nonlysosomal proteolysis. In the nucleus, ubiquitin is conjugated to histone 2A and may play a role in regulation of chromatin structure and/or regulation of transcriptional activity. During attempts to identify a cDNA encoding somatomedin-C (insulin-like growth factor I) we screened a fetal human liver cDNA library with a mixture of 17 base oligonucleotides corresponding to a portion of the B chain of somatomedin-C. One oligonucleotide of the mixture hybridized to two cDNAs encoding ubiquitin despite a 2-base pair mismatch. Nucleotide sequence analyses of the 350- and 516-base pair cDNAs revealed that they correspond to the same ubiquitin mRNA. The coding sequence of the 516-base pair cDNA begins at amino acid 5 of the ubiquitin sequence and encodes amino acids 5 through 76 of ubiquitin, an 80-amino acid carboxy-terminal extension, a 3' untranslated region, and a poly(A) tail. The finding that ubiquitin is synthesized as a precursor raises the possibility that the precursor sequence may be important in compartmentalization of ubiquitin or ubiquitin precursors. Analyses of ubiquitin mRNAs in poly(A) RNA extracted from human liver and various rat tissues reveals that there are three distinct mRNAs encoding ubiquitin in humans and four mRNAs in the rat.
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PMID:Nucleotide sequence analysis of a cDNA encoding human ubiquitin reveals that ubiquitin is synthesized as a precursor. 258 67

Ubiquitin was modified with the anionic, arginine-specific reagent 4-(oxoacetyl)phenoxyacetic acid in order to study the relationship between structure and function of the molecule. Four different derivatives (A, B, C, and D) were purified from the reaction mixture by anion-exchange high-performance liquid chromatography and subjected to tryptic peptide mapping to determine the location of the modification(s). These derivatives were stable throughout the procedures required for purification, tryptic hydrolysis, and peptide mapping. Derivative A was modified at arginine-42, derivative B at arginine-72, derivative C at arginines-42 and -72, and derivative D at arginine-74. Modification of ubiquitin with 14C-labeled 4-(oxoacetyl)phenoxyacetic acid indicated that the reagent formed a stable, 1:1 complex with arginine residues of the protein. Native ubiquitin and each of the four derivatives were tested for their ability to stimulate 32P exchange between ATP and pyrophosphate, a reaction catalyzed by enzyme 1 of the ubiquitin-dependent proteolytic pathway. A and C were capable of promoting this exchange at a rate only 15% that of native ubiquitin, B stimulated the exchange to 25%, and D stimulated exchange to 60% of the native level. None of the derivatives was capable of promoting a significant level of ubiquitin-dependent proteolysis. D was capable of forming conjugates with exogenous and endogenous proteins to an extent very similar to that of native ubiquitin, suggesting that its inability to stimulate ubiquitin-dependent proteolysis was due to a defect in a step beyond that of conjugate formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Structure and function of ubiquitin: evidence for differential interactions of arginine-74 with the activating enzyme and the proteases of ATP-dependent proteolysis. 282 40

Ubiquitin was purified from chicken testis and its content, biosynthesis and formation of conjugates was determined in germinal cells at successive stages of spermatogenesis. Free ubiquitin increased markedly during spermatogenesis, reaching its maximum level in early spermatids. High levels of ubiquitin were still present in late spermatids but were not detectable in mature spermatozoa. Biosynthesis of ubiquitin occurred in vitro in a fraction containing meiotic and pre-meiotic cells, and during spermiogenesis, in early and late spermatids. The cellular content of free ubiquitin increased after ATP depletion, especially in early spermatids. Lysates of chicken testis cells, particularly those obtained from spermatids, were able to form nuclear (24 and 27 kDa) and extranuclear (55-90 kDa) ubiquitin conjugates in vitro. The presence of increasing levels of ubiquitin and ubiquitin conjugates in chicken spermatids may suggest a possible involvement of this protein in the marked changes of protein turnover, chromatin structure and cell-cell interactions that spermatids undergo during spermiogenesis.
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PMID:Cellular content of ubiquitin and formation of ubiquitin conjugates during chicken spermatogenesis. 283 50

Ubiquitin, a 76 amino acid protein, is covalently attached to abnormal and short-lived proteins, thus marking them for ATP-dependent proteolysis in eukaryotic cells. Free (unconjugated) ubiquitin was localized in hepatoma cells using affinity purified anti-ubiquitin antibodies and colloidal gold immunoelectron microscopy. The anti-ubiquitin antibodies recognize only unconjugated ubiquitin. Ubiquitin is found within the cytoplasm, nucleus, the microvilli, autophagic vacuoles and lysosomes.
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PMID:Immunoelectron microscopic localization of ubiquitin in hepatoma cells. 284 72

Soluble, cell-free extracts of BHK 21/C13 fibroblasts degraded a variety of exogenous proteins to acid-soluble peptides at pH 8.0. ATP stimulated the rates of proteolysis. Both the absolute rate of proteolysis and the magnitude of the ATP effect depended on the specific substrate. For example, casein was degraded approximately 10-fold faster than lysozyme, but lysozyme degradation was more highly stimulated by ATP than was casein degradation. Ubiquitin enhanced the ATP-stimulated proteolysis of each substrate in both postmicrosomal extracts and DEAE-cellulose fractionated extracts. In each extract, ubiquitin enhanced the ATP-stimulated degradation of lysozyme to a greater degree than that of casein. These results suggested that lysozyme was degraded by a pathway that was more dependent upon ubiquitin than was casein. Further evidence for this conclusion was obtained in studies using substrates whose amino groups were blocked by extensive methylation or carbamoylation. The high molecular weight proteinase, macropain, appears to be involved in the ATP-stimulated degradation of both substrates. Specific immunoprecipitation of macropain with polyclonal antibodies resulted in the inhibition of ATP-stimulated proteinase activity both in the absence and presence of ubiquitin. These results indicate that macropain plays a role in both ubiquitin-mediated and ubiquitin-independent ATP-stimulated proteolysis in BHK cell extracts.
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PMID:An enzyme related to the high molecular weight multicatalytic proteinase, macropain, participates in a ubiquitin-mediated, ATP-stimulated proteolytic pathway in soluble extracts of BHK 21/C13 fibroblasts. 284 2

Protein degradation via the nonlysosomal ATP-dependent pathway in rabbit reticulocytes involves a number of components. In the initial event, ubiquitin, an abundant 76-residue polypeptide, becomes covalently linked to the protein substrate in an ATP-requiring reaction. Once marked in this way, the conjugated protein is proteolyzed in a reaction that also requires ATP. Ubiquitin-marking appears to be important to the progression of cells from one stage to another of the cell cycle; it may also be involved in gene activation. Here we show that tRNA is another essential component of the system. Ribonucleases strongly inhibit the ubiquitin- and ATP-dependent degradation of 125I-labeled bovine serum albumin in the reticulocyte system in vitro. RNAs extracted from fractions of the reticulocyte extract or from mouse cells restore proteolytic activity. When the RNA is fractionated by gel electrophoresis, only the tRNA fraction is active in restoring proteolysis. Furthermore, pure mouse tRNAHis, isolated by immunoprecipitation with patient autoimmune sera, restores the proteolytic activity. The possibility that the level of uncharged tRNA in mammalian cells regulates the ubiquitin- and ATP-dependent proteolytic system is discussed.
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PMID:Transfer RNA is an essential component of the ubiquitin- and ATP-dependent proteolytic system. 298 38


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